U.S. patent number 5,043,335 [Application Number 07/557,299] was granted by the patent office on 1991-08-27 for indolocarbazoles and the use thereof.
This patent grant is currently assigned to Godecke Aktiengesellschaft. Invention is credited to Johannes Hartenstein, Jurgen Kleinschroth, Claus Rudolph, Christoph Schachtele.
United States Patent |
5,043,335 |
Kleinschroth , et
al. |
August 27, 1991 |
Indolocarbazoles and the use thereof
Abstract
The present invention provides
9,10,11,12-tetrahydro-9,12-epoxy-1H-diindolo [1,2,3-fg:
3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H)-dione and
9,10,11,12-tetrahydro-2-(tetrahydro-5-methoxy-2-furanyl)
-9,12-epoxy-1H-diindolo[1,2,3-fg:
3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H)-dione process
for the preparation thereof, pharmaceutical compositions containing
the compounds, and use of the compounds in heart and blood vessel
diseases such as thromboses, arterioscleroses, hypertension and
inflammatory diseases, allergies, cancer and certain degenerative
damage of the central nervous system, as well as diseases of the
immune system.
Inventors: |
Kleinschroth; Jurgen
(Denzlingen, DE), Hartenstein; Johannes
(Stegen-Wittental, DE), Schachtele; Christoph
(Freiburg, DE), Rudolph; Claus (Vurstetten,
DE) |
Assignee: |
Godecke Aktiengesellschaft
(Berlin, DE)
|
Family
ID: |
6385761 |
Appl.
No.: |
07/557,299 |
Filed: |
July 23, 1990 |
Foreign Application Priority Data
|
|
|
|
|
Jul 25, 1989 [DE] |
|
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3924538 |
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Current U.S.
Class: |
514/211.08;
540/545 |
Current CPC
Class: |
A61P
7/02 (20180101); A61P 25/00 (20180101); A61P
43/00 (20180101); C07D 498/22 (20130101); A61P
29/00 (20180101); A61P 37/02 (20180101); A61P
25/28 (20180101); A61P 35/00 (20180101); A61P
9/10 (20180101); A61P 37/08 (20180101); A61P
9/00 (20180101); A61P 37/00 (20180101); A61P
9/12 (20180101) |
Current International
Class: |
C07D
498/00 (20060101); C07D 498/22 (20060101); C07D
498/12 (); A61K 031/55 () |
Field of
Search: |
;514/211 ;540/545 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Biomedical and Biophysical Research Communications, vol. 135, No.
1, 1986, pp. 297-303; Isolation and Characterization of a
Carcinoma-Associated Antigen, A. H. Ross et al. .
Heterocycles, vol. 21, No. 1, 1984, pp. 309-324 Natural Product
Synthesis via Cycloadditions with N-Sulfinyl Dienophiles, S. M.
Weinreb et al. .
The Journal of Organic Chemistry, vol. 52, No. 7, 1987 Synthesis of
the Aromatic and Monosaccharide Moieties of Staurosporine, R. P.
Joyce et al. .
Journal of Organic Chemistry, vol. 54, 1989, pp. 824-828 Synthesis
of Indolo[2,3-a]Pyrrolo[3,4-c]Carbazoles by Double Fischer
Indolizations, J. Bergman et al. .
Tetrahedron Letters, vol. 24, No. 13, pp. 1441-1444, 1983 Synthesis
of Arcyriaflavin B, I. Hughes et al..
|
Primary Examiner: Bond; Robert T.
Attorney, Agent or Firm: Anderson; Elizabeth M.
Claims
We claim:
1. A compound named
9,10,11,12-tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[
3,4-i][1,6]benzodiazocine-1,3(2H)-dione.
2. A compound named
9,10,11,12-tetrahydro-2-(tetrahydro-5-methoxy-2-furanyl)-9,12-epoxy-1H-dii
ndolo
[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H)-dione.
3. A pharmaceutical composition comprising a therapeutically
effective amount of a compound as defined in claim 1 or claim 2 in
combination with a pharmaceutically acceptable carrier.
4. A method for treating heart and blood vessel diseases which
comprises administering to a mammal in need of such treatment a
composition according to claim 3 in unit dosage form.
Description
BACKGROUND OF THE INVENTION
Protein kinase C plays an important role in intracellular signal
transduction and is closely linked with the regulation of
contractile, secretory, and proliferative processes.
SUMMARY OF THE INVENTION
The present invention concerns novel compounds ##STR1##
The invention also concerns pharmaceutical compositions containing
these compounds in an amount effective for treating heart and blood
vessel diseases. Such diseases are thromboses, arteriosclerosis,
and hypertension. It also includes composition for treating
inflammation, allergies, cancer, and certain degenerative damage of
the central nervous system as well as diseases of the immune
system.
The invention also concerns a method for treating heart and blood
vessel diseases such as thromboses, arterioscleroses, and
hypertension. It also includes methods for treating inflammation,
allergies, cancer, and certain degenerative damage of the central
nervous system as well a diseases of the immune system.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is concerned with the indolocarbazole
9,10,11,12-tetrahydro-9,l2-epoxy-1H-diindolo[1,2,3-fg:
3',2',1',kl]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H)-dione (I), as
well as pharmaceutical compositions containing this compound and
the derivative thereof substituted by a
5-methoxy-tetrahydrofuran-2-yl radical on the imide nitrogen atom,
i.e., 9,10,11,12-tetrahydro-2-(tetrahydro-5-methoxy-2-furanyl)
-9,12-epoxy-1H-diindolo[1,2,3-fg:-3',2',1'-kl]pyrrolo
[3,4-i][1,6]benzodiazocine-1, 3(2H)-dione (II), obtained in the
preparation of (I).
N,N-glycosides of indolocarbazoles are described in the literature
as inhibitors of serine/threonine protein kinase. Staurosporin, an
alkaloid glycoside of microbial origin, is compound of this class
(see Biochem. Biophys. Res. Commun., 135, 297/1986). A disadvantage
of this very potent inhibitor is that it inhibits the various
serine/threonine-specific protein kinases, such as protein kinase C
and the cAMP- and cGMP-dependent protein kinases, to the same
extent.
Surprisingly, it has been found that the compounds of the present
invention, in contradistinction to staurosporin, display a high
selectivity for protein kinase C. The compound ##STR2## has been
described in the literature. It differs from the compound of the
present invention by a benzyl substituent on the imide nitrogen
(see Heterocycles, 21, 309/1984). The literature does not disclose
an inhibitory effectiveness towards protein kinases. Comparative
experiments (see the following Table 1) show that under the same
conditions of the in vitro enzyme assay, at a concentration of
10.sup.-5 M, the compound (III) does not display a significant
inhibition of protein kinase C. The extraordinary increase of
potency in the case of going from the N-benzyl compound (III) to
the compound (I) unsubstituted on the imide nitrogen was
surprising.
The preparation of the compound of the present invention takes
place by a process analogous to that described in Heterocycles, 21,
309/1984 by the reaction of
indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione ##STR3## with
2,5-dimethoxytetrahydrofuran in the presence of an acidic catalyst,
a halogenated hydrocarbon, for example, dichloromethane or
1,2-dichloroethane, preferably used as solvent. As catalysts, there
are especially preferred p-toluenesulphonic acid and ferric
chloride hexahydrate.
The synthesis of the above indolocarbazole used as starting
material is described in the literature (Tetrahedron Lett., 24,
1441/1983; J. Org. Chem. 52, 1177/1986; J. Org. Chem., 54,
824/1989.
The inhibition of protein kinase C activated with
phosphatidylserine and diacylglycerol was determined according to
United States Patent 4,855,489, which is hereby incorporated by
reference. The determination the inhibition of the cAMP- and of the
cGMP-dependent protein kinase took place according to the test
description below.
TABLE 1 ______________________________________ Inhibiton (IC.sub.50
; .mu.M) IC.sub.50 kinase C- A- G- Ratio IC.sub.50 C-Kinase
Compound Kinase Kinase Kinase A/C G/C
______________________________________ I 0.028 5.5 0.52 196 19
Staurosporin 0.013 0.04 0.018 3.1 1.4 III >10
______________________________________
Protein kinase C plays an important key role for the intracellular
signal transduction and is closely linked with the regulation of
contractile, secretory, and proliferative processes. On the basis
of these properties, the compound according to the present
invention can be used for the treatment of heart and od vessel
diseases, such as thromboses, arterioscleroses, hypertension and
inflammatory processes, allergies, cancer, and certain degenerative
damage of the central nervous system, as well as of diseases of the
immune system. The compound can be administered enterally or
parenterally in the particularly suitable formulation in doses of 1
to 100 mg/kg of body weight and preferably of 1 to 50 mg/kg of body
weight.
Description of the Test for G Kinase and A Kinase
cGMP-dependent protein kinase: The enzyme was obtained from bovine
lung tissue and purified and its activity determined via the
incorporation of phosphorus 32-labeled phosphate into histone. The
following components are contained in a test batch of 200 .mu.L: 20
mM Tris-HCl (pH 7.4), 5 mM magnesium chloride, 1 mM DTT, 10 .mu.M
ATP, 10 mM cGMP, 40 .mu.g BSA, 2% glycerol, as well as 10 .mu.g
histone II-A and possibly the substance to be investigated. The
batch is preincubated without enzyme for 4 minutes at 30.degree. C.
and the reaction started by the addition of 2.5 nM G kinase. After
incubating for 5 minutes at 30.degree. C., the reaction is stopped
by the addition of 10% trichloroacetic acid and the samples then
filtered off over a nitrocellulose filter. The phosphate
incorporation is determined by Cerenkov counting in a scintillation
counter and the percentage inhibition calculated therefrom.
cAMP-dependent protein kinase: The measurement of the activity
takes place with the commercially available catalytic subunits of
the enzyme. The incorporation of phosphorus 32-labeled phosphate
into histone is thereby measured. A reaction batch of 200 .mu.L
contains the following components: 50 mM PIPES-NaOH (pH 7.5), 10 mM
magnesium chloride, 1 mM DTT, 40 .mu.M ATP, as well as 50 .mu.g
histone H-2B. The test is carried out as in the case of G kinase.
The reaction is thereby started by the addition of 6 units of the
catalytic subunit of the cAMP-dependent protein kinase.
The following example is given for the purpose of illustrating the
present invention:
EXAMPLE 1
9,10,11,12-Tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:
3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H)-dione
A suspension of 500 mg (1.54 mMol)
indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-(6H)-dione in 25 mL
dichloromethane is mixed with 3 mL (23 mMole)
2,5-dimethoxytetrahydrofuran, as well as 20 mg p-toluenesulphonic
acid and stirred for 5 days at 20.degree. C. The solvent is then
distilled off and the residue partitioned between 400 mL ethyl
acetate and 100 mL water. The ethyl acetate phase is separated off,
dried with anhydrous sodium sulphate, and evaporated. The residue
is chromatographed on silica gel with toluene/ethyl acetate (3:1
v/v). The fraction with the Rf of 0.45 is isolated and stirred with
diisopropyl ether/ethyl acetate.
9,12-Epoxy-1-oxo-1H-2,3,9,10,11,12-hexahydrodiindolo[1,2,3-fg:3',
2', 1'-kl]pyrrolo [3,4-i][1,6]benzodiazocine (I) is obtained in the
form of yellow crystals; mp>340.degree. C.
As by-product, in the case of the chromatography, the derivative
substituted on the imide nitrogen atom by a
5-methoxytetrahydrofuran-2-yl radical is obtained, i.e.,
9,10,11,12-tetrahydro-2-(tetrahydro-5-methoxy-2-furanyl)-9,12-epoxy-1H-dii
ndolo[1,2, 3-fg:3', 2', 1'-kl]pyrrolo
[3,4-i][1,6]benzodiazocine-1,3(2H)-dione (IV); Rf 0.5 in
toluene/ethyl acetate (3:1 v/v).
Spectroscopic data: MS (70 eV): m/z=393 (M.sup.+, 100), 321 (26);
IR (KBr):=3430, 1760, 1695, 1350, 1310, 740 cm.sup.-1 ; .sup.1
H-NMR (DMSO-d.sub.6 TMS):.delta.=2.04 (ps.increment.q, 2H,
CH.sub.2); 2.74 (m, 2H, CH.sub.2); 7.33 (m, 2H, CH); 7.43 (t, 2H,
J=7Hz, 8Hz, ArH); 7.63 (t, 2H, J=7Hz, 8Hz, ArH); 7.94 (d, 2H, J
=8Hz, ArH); 9.01 (d, 2H, J=8Hz, ArH).
* * * * *